Despite the enormous economic impact and substantial pain, suffering, and disability attributable to osteoarthritis (OA) of the knee, treatment remains entirely palliative; moreover, even with recent advances in analgesics, the majority of patients with symptomatic knee OA do not attain satisfactory long-term relief. Although the pathophysiology of OA is complex and incompletely understood, disease onset and progression are at least partly related to responses by bone and cartilage to normal as well as abnormal biomechanical loading, and many of these responses may be detected biochemically by assaying various serum and urine markers of joint metabolism. In OA of the knee, our previous SCOR studies have provided evidence that excessive loading of the medial compartment, as assessed by the external adduction moment, is associated with pain and with radiographic progression. Treatment with analgesia may relieve the pain but does not improve the biomechanics and may even exacerbate the process. Devices that promote reductions in the loading of the medial knee, however, may provide pain relief while simultaneously protecting the joint from further degeneration. One such device is a lateral wedge orthotic shoe insert; when worn during weight-bearing, these devices have been shown to reduce loading of the medial compartment and may provide pain relief. We propose to conduct a long-term randomized, double-blind, placebo controlled trial of lateral wedge orthotic inserts in medial knee OA to test the overall hypothesis that lateral wedge orthotics will relieve pain in knee OA, lower the external knee adduction moment, and alter the levels of serum biomarkers of bone and cartilage. The trial will include a 3 year treatment period; the primary outcomes to be sought include durable pain reduction without adverse clinical effects on the other joints of the lower extremities, a demonstrable relationship between pain reduction and the decreased loading provided by the wedge, and concomitant biochemical alterations in joint metabolism as assessed by serum and urine biomarker.